Modeling The Crosstalk Between The Circadian Clock Of Neurospora Crassa And ROS

The circadian clock is a kind of pace maker helping maintain a day/night cycle in creatures.It is a system with endogenous oscillation,entrainment and temperature compensation.The signal transduction network in circadian clock can produce oscillations with a period of about 24 hours.It can also sense the change of outer circumstances and adjust its phase and period to adapt to it.In addition,the circadian clock modulates the downstream clock-controlled genes to regulate other physiological behaviors.On the other hand,reactive oxygen species(ROS),recognized as a second messager,transmits signals to systems including the circadian clock.They have multiple interactions.Using modeling and numeric simulation,we describe the crosstalk between these two systems and reveal the underlying mechanism.It is the first work that intergrates these interactions observed experimentally.By parameter analysis and various simulation methods,we reveal the difference in the influence on the circadian clock between the post-translational and transcriptional regulation.The thesis consists of four chapters.In Chapter 1,we introduce biological backgrounds about circadian rhythm and ROS,including research history,function and feedback model of circadian clocks,new progress and issues,as well as different kinds of ROS,their functions and interactions with the circadian clock in Neurospora crassa.In Chapter 2,we build a model to characterize the interaction between the ROS and circadian clock.It was experimentally found that ROS may exert three kinds of effects on the circadian clock,improving the activity of PP2A,which can dephosphorylate WCC,promoting the binding of WCC to its target genes and repressing the dimerization of WC-1 and WC-2.WCC can up-regulate antioxidant enzymes such as catalase.We integrate these interactions and build an integrative model,aiming to reproduce and interpret experimental phenomena.We calculate the period and phase of circadian rhythm in both the deterministic and stochastic cases,and simulation results are consistent with experimental observations.These validate the model.In Chapter 3,we reproduce the change of period and phase shift and reveal the underlying mechanism.Experimentally,increasing the ROS level leads to a drop in the clock period under constant darkness,in contrast to phase advance under 12/12h dark-light entrainment.Perfoming numerical simulation,we reproduce those phenomena quantitatively.We find that the improvement of PP2A activity is the most significant manner for ROS to influence the circadian clock.The other two interactions with opposite effects on the period and phase may help maintain the system steady and stable.Consequently,the circadian clock can not only act quickly to a stimulus,but also avoid overeacting and be kept in control.In Chapter 4,we present a summary of our main results and give some outlooks for further research.